Gut-brain dysfunction following combined prenatal stressors: relevance for autism

Gastrointestinal issues are extremely common in neurodevelopmental disorders like autism spectrum disorder
(ASD), and alterations of the gut microbiome and intestinal epithelial barrier have been reported in recent studies.
Environmental toxicant exposures early in life are increasingly implicated in neurodevelopmental disorders such
as ASD, including air pollution. There is strong evidence that particulate matter (PM) in air pollution significantly
impacts the gut microbiome and gut function of directly-exposed humans and rodents. Less characterized is if
PM exposure to pregnant females alters the gut microbiome of offspring, though this is likely given evidence that
the maternal gut microbiome sets the trajectory of the newborn microbiome, especially with a vaginal delivery.
To study the impact of environmental pollutants on autism-like behaviors in mice, we developed a novel model
combining prenatal diesel exhaust particle (DEP) exposure throughout pregnancy with maternal stress (MS)
during the last trimester of gestation. Maternal stress is linked to autism in several recent studies, which may be
most harmful for populations made vulnerable by other factors. We have demonstrated that combined prenatal
DEP + MS produce striking communication and social deficits early in life, and persistent cognitive deficits and
increased anxiety into adulthood, in male but not female offspring. Our preliminary data also show significant
changes in the composition of gut bacteria and gut structural changes in male offspring exposed prenatally to
DEP/MS compared to unexposed controls. Our goal is to test the hypothesis that gut microbiome changes in
pregnant dams following combined environmental exposures are transmitted to newborn offspring and underlie
the persistent behavioral abnormalities. Together these studies will: (1) fully characterize the impact of prenatal
environmental toxicant (DEP) exposure on maternal and offspring microbiome development, (2) ascribe causality
among microbiota changes, gut epithelial structure/function and inflammation, and behavioral abnormalities in
offspring, and (3) establish the critical window(s) in which microbiome changes in offspring can be prevented or
reversed using interventions at birth vs. post-weaning. If successful they will significantly advance our
understanding of the emergence and causal link between gut dysbiosis and behavioral/brain dysfunction in
devastating disorders such as autism, and the role of environmental toxins in inducing these changes, as well
as suggest a potential therapeutic option and window for treatment.

Grant Number: 5R01ES033056-05
NIH Institute/Center: NIH
Principal Investigator: Staci Bilbo